Lung immaturity, diminished lung growth, and disordered repair after injury constitute major etiologies of pulmonary morbidity and mortality in the newborn period. The insulin-like growth factors (IGF-1 and -II) are important regulators of growth in the developing lung. IGF binding proteins (IGFBPs) are a group of highly regulated and abundant proteins that bind IGFs and control of IGFs and control of IGF bioavailability. Because of the central role IGFs play in maintaining cell cycle progression regulation of IGF activity by IGFBPs provides a mechanism for many agents to control IGF-stimulated fetal lung cell proliferation and differentiation. preliminary results indicate that exogenous IGFBPs decrease DNA synthesis in both fetal lung fibroblasts and epithelial cells. Many growth factors appear to influence cell proliferation by altering IGF-1 activity through changes in IGFBP abundance. PDGF-BB, an important mitogen during lung development, regulates IGFBP-4 production by fetal rat lung cells. Moreover, stimulation of IGFBP-4 by PDGF-BB results in inhibition of lung fibroblast proliferation. The proposed project tests the hypothesis that PDGF-BB regulates fetal rat lung cell proliferation, in part, by altering IGFBP-4 production. Thus, IGFBP-4 may directly affect lung organogenesis and may be a central mechanism by which the actions of multiple developmental and growth regulators are coordinated. To investigate these possibilities, I will examine how PDGF- BB and IGFP-4 interact to control fetal lung cell proliferation using primary cell cultures of lung fibroblasts throughout the canalicular and early saccular stages of lung development. This project will focus on the mechanism(s) involved in the stimulation of IGFBP-4 by PDGF-BB and the inhibition of DNA synthesis following PDGF-BB exposure and subsequent stimulation of IGFBP-4 production. The insights into IGFBP regulation during normal fetal lung cell proliferation generated by this research will add to our understanding of pulmonary cellular proliferation, and lung morphogenesis in general. Expanded knowledge of these processes is crucial to understanding aberrant lung development and altered lung growth after injury.